Research & Related Other Project Information Item 7. Project Summary/Abstract Neurodegeneration in Alzheimer's disease (AD) may result from deposition of A as plaques in brain tissue. However, less effort has been made to elucidate the role of tau- containing neurofibrillary tangles (NFTs) in AD. Accumulating evidence suggests that tau containing NFTs is an important component in the initiation and progression of AD and other neurodegenerative diseases. In this proposal the tau pathway is targeted through inhibition of the molecular chaperone Hsp90 as a promising new approach to affect the disease progression of AD. The goal of this grant is to optimize two structurally distinct scaffolds aided by in silico modeling and physical-chemical property predictions in order to generate novel brain permeable Hsp90 inhibitors as AD therapeutics. Subsequently, these compounds will be clinically developed for the treatment of AD using CSF biomarkers, as well as improved cognition, for in vivo efficacy determinations. PUBLIC HEALTH RELEVANCE: Research & Related Other Project Information Item 8. Project Narrative This research is focused on identifying potential drug candidates to treat Alzheimer's disease (AD) and in this way it addresses NIA's priorities to support research on health and disease in the aged. Furthermore, this project targets the tau pathway as a promising new approach to affect the disease progression of AD.